tbuckley/cabot-search huggingface dataset:
Update on phase 1 study of tazemetostat, an enhancer of zeste homolog 2 inhibitor, in pediatric patients with relapsed or refractory integrase interactor 1–negative tumors.
Authors: Susan N. Chi, Franck Bourdeaut, Michela Casanova, Lindsay Baker Kilburn, Darren R. Hargrave, Geoffrey Brian McCowage, Navin R. Pinto, Jay Yang, Raminder Chadha, Bhaskar Kahali, Coya Tapia, Karsten Nysom
Journal: Journal of Clinical Oncology (2022)

10040 Background: A defining feature of malignant rhabdoid tumors (MRTs), epithelioid sarcoma (ES), and poorly differentiated chordomas (PDC) is loss of integrase interactor 1 (INI1) expression, which induces dependence on enhancer of zeste homolog 2 (EZH2). Tazemetostat (TAZ) is a selective EZH2 inhibitor approved by the US Food and Drug Administration for patients (pts) aged ≥16 y with metastatic or locally advanced ES ineligible for complete resection. Pediatric dose escalation and interim efficacy and safety data for the dose expansion were previously reported. Updated efficacy, safety, subgroup analyses, and translational results are reported here. Methods: NCT02601937 is a phase 1 multicenter study evaluating TAZ monotherapy ≤2400 mg/m 2 daily in pediatric pts with relapsed or refractory INI1 − tumors (MRT, atypical teratoid rhabdoid tumor [ATRT], select tumors with rhabdoid features, other INI1 − tumors, and SS18-SSX synovial sarcoma). Primary endpoint for dose expansion was objective response rate (ORR). Secondary endpoints included safety/tolerability, duration of response (DOR), progression-free survival (PFS), and overall survival. Selected exploratory flow data using 250,000 cells from peripheral blood were available for up to 25 pts. Results: Phase 1 enrolled 109 pts (escalation, n=46; expansion, n=63; Table) with mean ages of 5.4 y in the dose escalation and 7.4 y in the dose expansion. ORRs were 7% (3/46) in the dose escalation and 14% (9/63) in the dose expansion. Per tumor category in the dose expansion, ORRs were 24% (5/21) ATRT, 33% (2/6) PDC, 22% (2/9) ES, and 0% in non–CNS RTs (n=21) and other tumors (n=6). ORR for pts with prior radiotherapy was 14% (11/80) vs 3% (1/29) with prior radiotherapy ( P&gt;0.05). In the dose expansion, median PFS was 8 wk (95% CI: 8–13), OS was 21 wk (95% CI: 13–38), and DOR was 35 wk (95% CI: 24–121). Grade 3–4 treatment-related treatment-emergent adverse event rates were 15% (7/46) in the dose escalation and 22% (14/63) in dose expansion. Differences between responders (R) and nonresponders (NR) at C1D1 for neutrophil counts were significant ( P&lt;0.05). All R (6/6) had &lt;125,000 total neutrophils at C1D1 vs 42% (8/19) of NR; 50% (3/6) of R had &gt;50,000 total CD3 T cells vs 0% (0/19) of NR. Conclusions: TAZ showed promising antitumor activity in ATRT, ES, and PDC. Potential synergism between prior radiotherapy and TAZ requires further investigation. TAZ was generally well tolerated. The biological/clinical significance of differences in peripheral blood cell counts between R and NR at C1D1 needs further investigation. Clinical trial information: NCT02601937. [Table: see text]
Competing endogenous RNA network features and prostate tumor cell sensitivity to radiotherapy.
Authors: Denis S. Kutilin, Mikhail S. Zinkovich, Marina A. Gusareva, Aleksey N. Shevchenko, Aleksandr V. Faenson, Anna A. Solntseva, Natalya B. Fatkina, Ekaterina O. Vasilieva, Elena V. Filatova, Natalia G Kosheleva, Ekaterina A. Tolmacheva, Ksenia V. Martynova, Madina A. Gappoeva, Irina A. Udalenkova, Irina A. Khomutenko, Lyudmila Ya Rozenko, Inna V. Pavlyatenko, Astanda K. Gvaramiya, Oleg I. Kit
Journal: Journal of Clinical Oncology (2022)

e17008 Background: Radiotherapy (RT) is one of the main treatments for prostate cancer (PC). The effectiveness of RT depends on the initial radioresistance of tumor cells provided by their certain molecular features - the transcriptional activity of genes, miRNAs and long non-coding RNAs (lncRNAs). Together, these indicators form a competing endogenous RNAs network (ceRNAs). The aim of this work was to study the ceRNA features in PC patients with different responses to RT. Methods: The study included 400 patients with PC, 90 of them developed biochemical recurrence after RT (Novalis TX, TFD = 75 Gy). Tumor tissue samples were obtained by biopsy. The RNA fraction was isolated and purified using the RNeasy Plus Universal Kits. Bioinformatic search for miRNAs was performed using a modified TarPmiR algorithm. The miRNA-lncRNA interactions were assessed by bioinformatics. Expression of AKT, ATM, BRIP, BRCA1/2, CDK1, CDKN1B, CCND1/3, EXO1, H2AX, KU70, PTEN, RAD50, RAP80, RIF1, RNF168, TOPB1, TP53, XRCC4, BAX, CASP-8, -3, -9, MDM2, BCL2, RBBP8, EP300 genes, miRNA and lncRNA were determined by RT-qPCR. Differences were assessed using the Mann-Whitney test (Bonferroni correction was used). Results: The expression of CDK1, CDKN1B, RBBP8, XRCC4, BRCA2, RAD50 genes in tumor tissues of patients with biochemical recurrence (group 1) was higher (p &lt; 0.005) and the expression of TP53 and BCL2 was lower than the values in tumor tissues in patients without recurrence (group 2). Bioinformatic search for miRNAs targeting the CDK1, CDKN1B, RBBP8, XRCC4, BRCA2, RAD50, TP53 and BCL2 revealed 1725 miRNAs, 78 of which were validated (miRDB) and had a minimum free energy of miRNA-mRNA interaction. Patients in group 1 showed differential expression of miRNAs targeting genes BCL2 (increased miR-139-5p, miR-4446-5p, miR-211-5p); CDK1 (decreased miR-330-3p, miR-5580-3p, miR-429), CDKN1B (decreased miR-6841-3p); RAD50 (decreased miR-433-3p, miR-3691-5p); RBBP8 (decreased miR-130b-3p); TP53 (increased miR-6884-5p, miR-149-3p, miR-6860, miR-4728-5p, let-7b-5p); XRCC4 (decreased miR-4489) and BRCA2 (decreased miR-7151-3p). The interaction of these miRNAs with 160 lncRNAs was mathematically predicted. Patients in group 1 demonstrated increased expression of lncRNAs LINC00641, SCAMP1, MALAT1, MATN1-AS1 (miR-429) , LINC00657 and GAS5 (miR-433-3p), CCAT1 (miR-130b-3p) and reduced expression of S NHG3, DHRS4-AS1 (miR-139-5p) and MAL2 (let-7b-5p). Conclusions: Our study of the ceRNA network features and RT effectiveness for PC established the mechanisms of radioresistance development and its predictors.
The development of APS03118, a potent next-generation RET inhibitor for treating RET-inhibitor-resistant patients.
Authors: Vivek Subbiah, Jun Zhong, Ying Lu, Yongbo Liu, Minchun Chen, Xiaohu Chen, Hao Wang, John Zhu, Shun Lu, Alexander E. Drilon
Journal: Journal of Clinical Oncology (2022)

e15107 Background: Oncogenic RET is an actionable target across a variety of cancers. Selective RET inhibitors selpercatinib and pralsetinib were recently approved by the FDA and EMA for patients with RET-dependent NSCLC and thyroid cancers. The solvent front mutations (SFMs) RET G810C/S/R have been identified as mechanisms of acquired resistance to both drugs. APS03118 is a novel next-generation RET inhibitor which is potent against a range of RET fusions and mutations including both SFMs and gatekeeper mutations. Methods: The selectivity, anti-RET activity, and intracranial efficacy of APS03118 were confirmed in vitro and in vivo in a variety of RET-dependent tumor models. Results: APS03118 was highly selective against a panel of 468 kinases and demonstrated 130-fold selectivity over VEGFR-2. In enzymatic assays, APS03118 showed low nanomolar potency against wild type RET and 25 RET mutations/fusions, including the inhibition of RET G810R/C/S (IC 50 0.04-5 nM) and RET V804M/L/E (IC 50 0.04-1 nM). APS03118 inhibited RET phosphorylation (IC 50 &lt; 15 nM) in Ba/F3 engineered RET cells (WT, G810R, V804M, M918T). In cell proliferation assays, APS03118 potently inhibited the proliferation of KIF5B-RET Ba/F3 (WT, V804M, V804L, M918T), CCDC6-RET Ba/F3 (WT, V804M, S904F), LC2/ad (CCDC6-RET), TT (RET C634W) (IC 50 &lt; 10nM); Ba/F3 RET G810R and G810S IC 50 (8-65 nM). APS03118 demonstrated marked anti-tumor efficacy in vivo in RET-driven cell-derived (Ba/F3 KIF5B-RET, V804M, TT (C634W)) and patient-derived (KIF5B-RET, CCDC6-RET, CCDC6-RET V804M) xenograft tumor models at 10 mg/kg (TGI 87-108%). Tumors completely subsided in CCDC6-RET orthotopic brain model with a 100% survival rate. In the Ba/F3 KIF5B-RET G810R xenograft model, APS03118 30 mg/kg showed 90% TGI and was well tolerated, and RET G810 mutations often drive clinical progression on current RET inhibitors. The pharmacokinetic/pharmacodynamic relationship of APS03118 in Ba/F3 KIF5B-RET G810R and WT xenograft tumor model was investigated, and the sustained decrease of the phosphorylated RET were observed at 30 mg/kg with the plasma exposure exceed cell IC 90 . Conclusions: APS03118 is a novel highly selective next-generation RET inhibitor that possesses potent in vitro and in vivo activity against a diverse range of RET alterations, including SFMs-mediated resistance. APS03118 has received IND approval and Fast Track Designation from FDA, and a first-in-human phase 1 trial for patients with RET-driven solid tumors with activating RET alterations is planned for 2022.
The need for artificial intelligence curriculum in medical education: A Canadian cross-sectional study of future oncology trainees.
Authors: Aidan Pucchio, Raahulan Rathagirishnan, Natasha Caton, Peter Gariscsak, Joshua Del Papa, Vicky Vo, Wonjae Lee, Jacqueline J. Nabhen, Fabio Ynoe de Moraes
Journal: Journal of Clinical Oncology (2022)

e13583 Background: Emerging artificial intelligence (AI) technologies have diverse applications in medicine, with early evidence suggesting that AI tools can accurately perform key tasks in oncology. As AI tools advance towards clinical implementation, skills in how to use and interpret AI in a healthcare setting could become integral for physicians. This study seeks to assess exposure to AI in medical education among trainees interested in pursuing a career in oncology, and the need for AI education in medicine. Methods: A 32 question survey for Canadian undergraduate medical students was distributed to students at all 17 Canadian medical schools. The survey assessed the currently available and perceived need for learning opportunities about AI and barriers to educating about AI in medicine. Interviews were conducted with participants to provide narrative context to survey responses. Likert scale (LS) survey questions were scored from 1 (disagree) to 5 (agree), and analyzed using a two-sided one sample t-test vs a neutral value. Interview transcripts were analyzed using qualitative thematic analysis. Results are described as mean LS score ± standard deviation. Results: We received 486 responses from 17 of 17 medical schools. Of these respondents, 98 (20.2%) are willing to pursue a residency in an oncology-related field (pathology, radiology, general surgery, internal medicine, radiation oncology). Respondents agreed that AI applications in medicine would become common in the future (3.80±0.38) and would improve medicine (3.71±0.54). Further, respondents agreed that they would need to use and understand AI during their medical careers (3.76±0.572; 3.43±0.773), and that AI should be formally taught in medical education (3.43±0.756). In contrast, a significant number of participants indicated that they did not have any formal educational opportunities about AI (1.76±0.785) and that AI-related learning opportunities were inadequate (2.12±0.802). Interviews with 18 students were conducted. Emerging themes from the interviews were a lack of formal education opportunities and logistical challenges in adding AI to curriculum. Conclusions: A lack of educational opportunities about AI in medicine were identified across Canadian medical students. Given that medical students overwhelmingly believe that AI is important to the future of medicine, and AI tools are currently progressing towards clinical implementation, AI should be considered for inclusion in formal medical curriculum.
Patterns of care and survival of first line anti-EGFR therapy; results from South Australian (SA) metastatic colorectal (mCRC) registry.
Authors: Timothy Jay Price, Cynthia Piantadosi, Christos Stelios Karapetis, Amitesh Chandra Roy, Robert Padbury, David Roder, Barbara Geerinckx, Amanda Rose Townsend
Journal: Journal of Clinical Oncology (2022)

e15577 Background: Treatment of mCRC has changed dramatically over the last decade with therapy guided by clinical and molecular features which include side of primary, RAS, BRAF and MMR status. For left sided RAS WT mCRC survival is optimized by using first line anti-EGFR anti-bodies combined with chemotherapy. This is reflected in modern guidelines. Methods: We aim to assess the uptake of first line anti-EGFR/chemotherapy combinations in patients with mCRC and assess for difference between cetuximab (C) and panitumumab (P) use from the SAmCRCR. The real word registry has collected data from all patients diagnosed with mCRC in SA prospectively since 2/2006. We compared RAS WT patients treated with chemo/bevacizumab (CB). Survival was analysed using the Kaplan Meier method. Results: Of the 5537 patients currently entered onto the registry, only 97 had RAS status recorded and had received first line anti-EGFR/chemotherapy (FaEC). 102 patients were RAS WT and received CB. Table summarises patient characteristics and median OS for FaEC (C or P) and CB. There was no statistical difference in survival for C v P (p = 0.055). Conclusions: When comparing C &amp; P choice in first line therapy, C was more often combined with irinotecan/chemo. C patients had higher rate of left sided primary. There were lower rates of liver resection in patients treated with C which may explain the numerically lower median overall survival. An updated cohort analysis will be included to assess changes in practice over time.[Table: see text]
FDA analysis of expanded access use in pediatric patients from 2015 to 2020.
Authors: Elizabeth Duke, Natasha L. Kormanik, Amy Barone, Harpreet Singh, Julia A. Beaver, Richard Pazdur, Gregory H. Reaman, Martha Boeri Donoghue
Journal: Journal of Clinical Oncology (2022)

1529 Background: Expanded Access is a regulatory mechanism that enables patients with a life-threatening condition or serious disease to receive treatment with an investigational drug outside of a clinical trial when no comparable or satisfactory alternative options are available. FDA has decades of experience with expanded access, but little has been reported about its use in pediatric cancer patients. Methods: FDA’s central electronic database was queried for single-patient investigational new drug (spIND) applications submitted to the Office of Oncologic Diseases between January 2015 through December 2020. Data collection included IND receipt date, IND type/status, drug name, and patient demographics. Duplicate or exempt INDs, those cancelled by the physician-sponsor before initiating therapy, and those requested for indications that occur almost exclusively in adults (e.g. lung cancer) or were missing patient age were excluded. Results: Of 2,901 unique spINDs granted, 534 (18%) were for patients less than 18 years of age. The pediatric population was 57% male, median age 6.0 years (range 0.1 to 17); race/ethnicity were reported in &lt;1%. Patients were treated in 132 zip codes across 39 states; one-quarter of submissions were from 5 large academic hospitals. Central nervous system tumors were the most common indication (Table 1). A total of 98 unique drugs were requested, with 1 to 73 spINDs for each drug; approximately 50% were for tyrosine kinase inhibitors, 25% for other small molecules, and the remainder for immunotherapies and other drug types. Median time for FDA to grant was 1 day. Follow-up information was provided for 75% (annual report or withdrawal letter); 1/3 were withdrawn within 1 year. Over the last 2 years, utilization of the program increased by 120%. Conclusions: While approximately 1% of all cancers per year are diagnosed in children under 17 years of age, 18% of spINDs over the last five years were for pediatric patients. Although utilization of this program for children is robust, efforts are needed to assess its impact on patient outcomes and ensure its availability to patients, families, and institutions more widely. These data highlight interest within the pediatric oncology community in accessing innovative therapies, which supports early investigation of promising new drugs in children.[Table: see text]
TTI-621-03: A phase I/II study of TTI-621 in combination with doxorubicin in patients with unresectable or metastatic high-grade leiomyosarcoma (LMS).
Authors: Sant P. Chawla, Ciara Marie Kelly, Erlinda Maria Gordon, Doris V. Quon, Ania Moradkhani, Victoria S. Chua-Alcala, Theresa M. Thompson, Anita Scheuber, Ingmar Bruns, Victoria E. Allgood, Sujana Movva
Journal: Journal of Clinical Oncology (2022)

TPS11593 Background: Doxorubicin is a standard of care agent for patients with advanced soft tissue sarcoma, with a response rate of around 15%, progression-free survival of 5-7 months and cumulative cardiac toxicity that limits its use. TTI-621 is a recombinant soluble fusion protein that combines the N-terminal portion of human SIRPα (the binding domain for CD47) with the Fc region of human IgG1, generating a decoy receptor for CD47 on the surface of tumor cells that both over-rides CD47-mediated inhibition of phagocytosis and provides a pro-phagocytic stimulation. Many solid tumors express high levels of CD47 which is associated with poor prognosis, thought to be the result of CD47-mediated inhibition of macrophage phagocytosis and escape of immune-mediated clearance. Interruption of the CD47-SIRPα signaling pathway using monoclonal antibodies to CD47 has shown anti-tumor activity in animal models and in some early clinical trials. The combination of doxorubicin with CD47-targeted antibodies results in enhanced anti-tumor activity and increased macrophage-mediated cell killing in animal models and macrophage-mediated phagocytosis of cancer cell lines in vitro, suggesting that combining TTI-621 with doxorubicin might be more effective than doxorubicin alone in tumor types that express CD47 and have high numbers of macrophages, such as LMS. Thus, a Phase 1/2 study was initiated to evaluate this combination in patients with advanced soft tissue sarcoma, including LMS. Methods: TTI-621-03 is a Phase 1/2, open-label study of TTI-621 in combination with doxorubicin in patients with anthracycline-naïve disease. The Phase 1 dose escalation evaluates doses of TTI-621 (0.2 to 2.0 mg/kg) in combination with doxorubicin at 75 mg/m 2 in patients with high-grade soft tissue sarcomas. Expansion cohorts will evaluate TTI-621 (0.2 and 2.0 mg/kg) with doxorubicin in patients with LMS, with pathology confirmed at a central laboratory. The primary goals of this study are evaluation of safety of TTI-621 administered in combination with standard-of-care doxorubicin and to further evaluate clinical activity (ORR, PFS, OS), safety, PK and patient-reported quality of life in the LMS subpopulation. The dose escalation portion of the study has been completed without DLT. Enrollment to the expansion portion of the study is underway. Clinical trial information: NCT04996004.
The pattern of KRAS mutations in non-small cell lung cancer (NSCLC): A retrospective study from south-eastern Georgia.
Authors: Sabrina Matosz, Mostafa Elzaidy, Nagla Fawzy Abdel Karim
Journal: Journal of Clinical Oncology (2022)

e15110 Background: Carcinogenic Kirsten rat sarcoma viral oncogene homolog (KRAS) mutation is a common oncogenic mutation found in lung cancer. It is a gain-of-function mutation that is the most commonly mutated oncogene in NSCLC; occurs in about 30% of all lung adenocarcinomas. A lot of progress has been made in targeted therapies against other oncogenic drivers, such as EGFR, HER2, MET, BRAF mutations. However, KRAS mutant lung cancer is still very difficult to manage and options are limited. Most recently, K-ras G12C has a newly approved novel targeted therapy. Different KRAS mutations may also represent different outcomes. Multiple studies have been looking into mutant KRAS and investigating it in the clinical relevance in lung cancer. Here we characterize a cohort of KRAS subtypes in all tumor types of lung cancer from south-eastern Georgia. Methods: This is a retrospective study that evaluated patients with K-ras mutant lung cancer from Augusta, Georgia geographical area. Samples were obtained from May 15 th , 2015 to January 4 th , 2022 and patients with KRAS mutant lung cancers were identified via Guardant platform. Results: In our cohort of patients, a total of 622 patients were evaluated in which 531 patients had a lung cancer diagnoses. Of those 531 patients, 383 had lung adenocarcinoma, 109 lung squamous cell, 34 NSCLC, 3 small cell, 1 lung carcinoid, and 1 large cell lung carcinoma. Of the 531 lung cancer patients, 14 (2.6%) patients expressed KRAS mutation with 12 (3.1%) patients expressing KRAS with lung adenocarcinoma. NRAS was expressed separately in 2 patients and HRAS was expressed separately in 1 patient. Our cohort of patients with K-ras mutant NSCLC had TP53 co-mutation in 78 (14%), MSI-High mutation in 60 (11%) patients, and EGFR mutation in 23 (4.3%) patients. The most common KRAS subtype in lung adenocarcinoma was G12V (42%), G12C (42%), and Y64D (8.3%). Two patients were unable to identify the type of the K-ras mutation. In addition, 92% of the carriers for KRAS mutation in lung adenocarcinoma were males. Its been noted that G12C mutation is the most common; however, in south-east Georgia, G12V is as common as G12C. Conclusions: KRAS mutation subtypes have distinct genomic landscape which requires further assessment to guide future therapeutic development. In the geographical area of Augusta, Georgia, KRAS subtype G12V is as common as G12C.